Ubiquitin-mediated signaling plays a central role in the control of protein degradation. Ubiquitin ligases synthesize polyubiquitin chains on target proteins, which are then degraded by the proteasome. The era of PROTAC drugs (proteolysis-targeting chimeras) was launched by the emergence of new concepts in medicinal chemistry, wherein small molecules are designed to contain groups that bind to a ubiquitin ligase at one end and to the target protein at the other end, leading to proteasome-mediated degradation of the target protein. PROTACs recruit cellular protein degradation machinery for polyubiquitination and subsequent proteasomal degradation. While this concept is quite promising, there are major hurdles in developing new PROTAC drugs. Medicinal chemists rapidly synthesize a variety of PROTAC molecules, which must then be tested in laborious cell-based assays to monitor degradation of target proteins by immunoblotting. The rate of development of novel PROTAC designs has surpassed the existing capacity to validate their ability to recruit respective E3 ligase(s) and candidate substrates and to effect polyubiquitination and degradation of the target. Currently, no efficient methods are available to validate the ubiquitination ability of newly designed PROTACs. Here we propose to develop a novel high-throughput method to screen polyubiquitination and degradation properties of PROTACs. This technology will help medicinal chemists to design PROTAC drugs in a rational way and accelerate the development of PROTACs in new therapeutic areas.